Urinary tract infection (UTI) is a widespread and costly disease caused mostly by Escherichia coli (E. coli). Traditionally, recurrent UTI was thought to be an acute disease resulting from repeated inoculation of bacteria into the urinary tract. Data from a mouse model suggest that it is instead a chronic condition caused by an intracellular reservoir of bacteria within the bladder, demanding different treatments. These two models make different predictions about changes in the evolutionary population size of the infecting bacteria. DNA sequencing of serial isolates from patients suffering from recurrent UTI will allow use of population genetics tests (1) to determine if the intracellular reservoir observed in mice occur also in humans and (2) to differentiate between these two models (external inoculation versus internal reservoir) for recurrent UTI. The population size changes observed in mice also suggest that genetic screens for new virulence factors are impractical. A more detailed molecular understanding of urinary tract pathogenesis requires new methods for identifying virulence factors. Sequence data will again be used (3) to identify positively selected genes in uropathogenic E. coli strains as new candidate virulence factors. [unreadable] [unreadable] [unreadable]